Understanding antibody responses and defining correlates of protection for endemic and pandemic coronavirus strains

The SARS-CoV-2 pandemic represents an exceptional public health crisis highlighting the need for better understanding of the mechanisms controlling broadly protective immune responses and generating vaccine candidates able to elicit such responses. The program project entitled "Programming Long-lasting Immunity to Coronaviruses (PLUTO)" proposes a comprehensive research plan towards designing pan- sarbecovirus and pan-betacoronavirus vaccines with broad protection by applying in-depth B cell characterization in the context of coronavirus immune histories imprinted by successive vaccinations and/or infections. Two complementary research projects will establish correlates of robust, durable and protective coronavirus humoral immunity (Project 1) as well as design and test efficacy of viral variant-proof pan-sarbecovirus and pan-betacoronavirus vaccines (Project 2). The Cores will synergize with the two research projects to support the successful completion of the research aims. The Administrative Core will manage the consortium, coordinate cross-project activities, and create the structure and environment needed to accomplish PLUTO's goals. The Antibody Core will develop large panels of recombinant monoclonal antibodies (mAbs) against coronavirus spike proteins to define specificity and breath of immune responses elicited by coronavirus infections and/or vaccinations in humans and animal models. The Animal Model Core will provide a central resource with approvals, facilities, and expertise to assess efficacy of broadly cross-reactive coronavirus antibodies and vaccines in robust pre-clinical models against a spectrum of coronaviruses, including Select Agents. The Research Projects will collaborate with each other and with the Antibody and Animal Model Cores, coordinated by the Administrative Core. Project 1 will focus on defining B cell responses to coronavirus infection and vaccination. In Project 1, we will pair exceptionally unique clinical specimens with our in-depth interrogation of B cell response dynamics at the single cell level and specificity at atomic resolution to provide a robust platform for identifying correlates of protective immunity. The resulting structural data will provide key information towards the development of a "universal" coronavirus vaccine (in collaboration with Project 2). A multidisciplinary team of scientists from five institutions who have an outstanding track record of working collaboratively will conduct the proposed studies. The integrated and synergistic activities across Projects and Cores will drive the successful completion of the program project's ambitious research agenda, enabling achievement of the long-term PLUTO goal of developing variant-proof pan-sarbecovirus and pan-betacoronavirus vaccines. These findings will contribute to curbing the current SARS-CoV-2 pandemic and mitigate the risk of future pandemics with coronaviruses.